Is FSHD Hereditary?
Yes, Facioscapulohumeral Muscular Dystrophy (FSHD) is hereditary, transmitted primarily as an autosomal dominant disorder, meaning an affected parent has a 50% chance of passing the condition to each child. 1, 2, 3
Inheritance Pattern
- FSHD follows autosomal dominant inheritance in the vast majority of cases, where only one copy of the mutated gene is sufficient to cause disease 2, 3
- A minority of cases (approximately 5-10%) demonstrate digenic inheritance, requiring genetic variants at two different loci for disease manifestation 3
- The disease shows variable penetrance, meaning not all individuals carrying the genetic mutation will develop symptoms, which complicates genetic counseling 4
Genetic Mechanism
- FSHD results from heterozygous partial deletion of D4Z4 repetitive elements on chromosome 4q35 in approximately 95% of cases 2
- The pathogenic deletion must occur specifically on the 4A161PAS haplotype to cause disease; deletions on other haplotypes typically do not result in FSHD 4
- The genetic defect leads to aberrant expression of the DUX4 gene in skeletal muscle, which codes for a transcription factor that causes muscle cell toxicity 1
Clinical Implications for Families
- Each child of an affected parent has a 50% risk of inheriting the mutation in typical autosomal dominant cases 2, 3
- Approximately 20% of FSHD cases represent de novo mutations, occurring spontaneously without a family history 2
- Wide variability exists even within the same family regarding age of onset, disease severity, and progression rate 2
Important Genetic Counseling Considerations
- Carriers of D4Z4-reduced alleles with the 4A161PAS haplotype may remain asymptomatic (non-penetrant), with studies showing 52.6% of single allele carriers in certain families showing no symptoms 4
- The population frequency of pathogenic D4Z4-reduced alleles is higher than expected based on disease prevalence (approximately 1.2%), suggesting incomplete penetrance 4
- Compound heterozygotes (carrying two different D4Z4-reduced alleles) have been identified, and in some families only these individuals manifest disease while single allele carriers remain unaffected 4
Practical Genetic Testing Approach
- Genetic testing should analyze both the D4Z4 repeat size and the specific 4q35 haplotype (4A161PAS versus non-permissive haplotypes) 4
- Haploinsufficiency alone (loss of the 4q telomeric region) does not cause FSHD, as demonstrated by phenotypically normal individuals with chromosomal translocations removing this region 5
- Epigenetic mechanisms, including altered DNA methylation patterns, play a critical role in disease pathogenesis beyond simple gene deletion 2
Common Pitfalls to Avoid
- Do not assume all individuals carrying a D4Z4-reduced allele will develop symptoms—penetrance is incomplete and influenced by haplotype context 4
- Do not provide overly simplistic genetic counseling stating 50% risk without discussing variable penetrance and the requirement for the permissive 4A161PAS haplotype 4
- Do not overlook the possibility of compound heterozygosity in families where multiple D4Z4-reduced alleles segregate, as this may explain unusual inheritance patterns 4